All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
Herbal Medicine
Herbal medicine has been in use for centuries by people of Asia and Europe. In the United States (US), herbs have become commercially valuable in the dietary supplement industry as well as in holistic medicine. Approximately one third of the US population has tried some form of alternative medicine at least once (Eisenberg et al., N. Engl. J. Med., 328:246-252 (1993)). Botanicals have also become a focal point for the identification of new active agents to treat diseases. Active compounds, derived from plant extracts, are of continuing interest to the pharmaceutical industry. For example, taxol an antineoplastic drug obtained from the bark of the western yew tree, has been found to be useful in the treatment of breast cancer (Gomez-Espuch et al., Bone Marrow Transplant, 25(3):231-235 (2000)).
There are many branches of herbal medicine around the world, such as Ayurveda, Unani, Sida and Traditional Chinese medicine (TCM). While modern Western medicine typically consists of administering a single chemical entity capable of intervening a specific biochemical pathway, each formula of TCM contains hundreds of chemical entities from several herbs which are designed to interact with multiple targets in the body in a coordinated manner. Although empirical practice contributed in a significant way to the herbal composition and prescription of these ancient herbal medicines, they are also supported, to a varying degree, by a set of theories which all are distinct from that of modern Western medicine in terms of anatomy, pharmacology, pathology, diagnosis treatment, etc. Among the different herbal medicine fields, TCM has developed a more complete set of theories over several centuries which have been well documented and practiced by local physicians caring for a huge population (>1.3 billion people) in greater China and in East Asia including Korea and Japan.
Traditional Chinese Medicine
Western medicine generally uses purified compounds, either natural or synthetic, mostly directed towards a single physiological target. However, the compositions used in TCM are usually composed of multiple herbs and compounds which are aimed at multiple targets in the body based on unique and holistic concepts. TCM mainly use processed crude natural products, with various combinations and formulations, to treat different conformations resulting in fewer side effects. The great potential of TCM has yet to be realized for the majority of the world's people.
Mixtures of botanical extracts, rather than a single compound are widely used throughout the world for the management of disease and are slowly gaining increased acceptance in Western countries (Okada, F., Lancet 348: 5-6(1996); Xiao P G, Xing S T and Wang L W, Journal of Ethnopharmacol 38: 167-175(1993)). The use of Traditional Chinese medicine is based on the interaction of many chemical components in an herbal preparation that act simultaneously and synergistically on multiple molecular targets and cellular mechanisms. These components serve various functions; some may be responsible for efficacy while others may decrease toxicity or increase bioavailability. Chinese herbal formulations are perhaps the best known botanical drugs and have been derived from empiric observations in humans over the millennia. The claimed indication of a given Chinese medicinal preparation, in many cases, is multiple rather than single. This is not surprising, due to the many phyto-chemical ingredients in a formulation that could exert actions at multiple targets. It is possible that one Chinese medicinal formulation may relieve more than one side effect associated with the use of cancer chemotherapeutic agents.
The herbs in a typical TCM prescription are assigned roles as the principal herb and the secondary herbs, including assistant, adjuvant and guiding herbs. The principal herb produces the leading effects in treating the cause or the main symptom of a disease. An assistant herb helps to strengthen the effect of the principal herb and produces leading effects in the treatment of the accompanying symptoms. There are three types of adjuvant herbs: 1) those that enhance the therapeutic effects of the principal and assistant herbs or treat tertiary symptoms, 2) those that reduce or eliminate the toxicity and other side effects of the principal and the assistant herbs and 3) those that act on complementary target tissues not specifically affected by the principal herb. A guiding herb directs the effect of other herbs to the affected site and/or coordinates and mediates the effects of the other herbs in the prescription or formulation. In contrast to most of the herbal medicines or supplements that consist of one or more parts of a single plant, the intended effects of TCM are directed at multiple tissues.
For example, a well-known TCM recipe, “Ephedra Decoction” used for treating asthma is composed of ephedra, cinnamon twig, bitter apricot kernel and licorice. Ephedra, as the principal herb, which expels cold, induces diaphoresis and facilitates the flow of the Lung Qi to relieve asthma, the main symptom. Cinnamon twig, as the assistant herb, enhances ephedra's induction of diaphoresis and warms the Channels to ensure the flow of Yang Qi for reducing headache and pantalgia. Bitter apricot kernel, as the adjuvant herb, facilitates the adverse flow of the Lung Qi and strengthens the asthma relief by ephedra. Licorice as the guiding herb moderates the effects of both ephedra and cinnamon to ensure a homeostasis of the vital Qi. While each of the four herbs clearly exhibits its respective activity, they complement as well as supplement each other when they are combined. In practice, the principal herb can be prescribed with one or more secondary herbs, depending on the symptoms at a patient's presentation (Prescriptions of Traditional Chinese medicine, Chapter One, pp 10-16, E. Zhang, editor in Chief, Publishing House, Shanghai University of Traditional Chinese medicine, 1998).
Qi refers to the total energy of the body. Herbs are used to achieve the optimum balance of Qi; that balance is believed to manifest itself in the overall health and vigor of the patient (K. C. Huang, The Pharmacology of Chinses Herbs, Second Edition, Page 2, 1999, CRC Press).
The main theories of TCM that guide the treatment of sickness with herbal medicine and other means, such as acupuncture, are 1) the theory of Yin and Yang; 2) the theory of Five Elements; 3) the theory of Viscera and Bowels; 4) the theory of Qi, Blood and Body Fluid; and 5) the theory of Channels and Collaterals.
In TCM, the first important aspect of making the proper diagnosis is to ascertain whether the disease is Yin or Yang, the two forces which the Chinese believe control the workings of the universe. Yin represents the feminine side of nature, encompassing darkness, tranquility, depth, cold, and wetness, while Yang represents a masculine principle, encompassing light, activity, height, heat, and dryness (K. C. Huang, The Pharmacology of Chinese Herbs, Second Edition, Page 2, 1999, CRC Press). Yin is commonly interpreted to be a negative force, while yang represents a positive force. The two forces are complementary, and neither can exist without the other. Thus, TCM attempts to achieve a balance between Yin and Yang.
In diagnosing a patient based on the philosophy of Yin and Yang, those patients who have a fever, are thirsty, constipated or have a rapid pulse condition are of Yang character. Those individuals who have an aversion to cold, are not thirsty, and diarrhea and a slow pulse condition are of Yin character. The property, flavor and function of herbs can also be classified according to Yin and Yang theory. For example, herbs of cold and cool nature belong to Yin, while herbs which are warm and hot in nature belong to Yang. Herbs with sour, bitter and salty flavor belong to Yin, while herbs with pungent, sweet and bland flavor belong to Yang. Herbs with astringent and subsiding function belong to Yin, while herbs with dispersing, ascending and floating function belong to Yang. In TCM, the principles of treatment are based on the predominance or weakness of Yin and Yang. Herbs are prescribed according to their property of Yin and Yang and their function for restoring the imbalance of the Yin and Yang. In so doing, the benefit of treatment is achieved.
According to the theory of Five Elements there are five basic substances that constitute the material world (i.e., wood, fire, earth, metal and water). In TCM this theory has been used to explain the physiology and pathology of the human body and to guide clinical diagnosis and treatment. Herbal physicians have applied the laws of generation, restriction, subjugation, and reverse restriction of the five elements to work out many effective and specific treatment regimens, such as reinforcing earth to generate metal (strengthening the function of the spleen to benefit the lung), replenishing water to nourish wood (nourishing the essence of the kidney to benefit the liver), supporting earth to restrict the wood (supplementing the function of the spleen to treat the hyperactivity of the liver), and strengthening water to control fire (replenishing the essence of the kidney to treat hyperactivity of the heart). Specifically, the property of some herbs is assigned to each of the five Elements for the purposes of guiding the prescription of a TCM recipe.
In TCM, the internal organs of the human body are divided into three groups: five Viscera (the Heart, the Liver, the Spleen, the Lung and the Kidney), Six Bowels (the Gall Bladder, the Stomach, the Large Intestine, the Small Intestine, the Urinary Bladder, and the Triple Warmer), the Extraordinary Organs (the Brain, the Medulla, the Bone, the Blood Vessel, the Gall Bladder, and the Uterus). In TCM, the Viscera or the Bowel are not only anatomic units, but also concepts of physiology and pathology concerning interactions among different organs. For example, the heart also refers to some of the mental functions and influence functions of blood, hair, tongue, and skin. Yin and Yang and the Five Elements influence the interactions among these internal organs, Viscera, Bowels, and Extraordinary Organs. The complexity of interplay of the theories is used to explain the pathology of diseases to which herbs are prescribed, as discussed below.
The prescription of herbal medicine in TCM starts with the diagnosis, which consists of four main items: interrogation, inspection, auscultation and olfaction, pulse taking and palpation. During the interrogation phase, much information is gathered, including the characteristics of the main symptoms. For instance, if the main symptom is characterized by the dull pain of the epigastric region, which may be relieved by warming and pressing, this suggests the insufficiency of the Spleen-Yang. Soreness and weakness of the loins and knees, intolerance of coldness with cold extremities manifests a weakness of the Kidney-Yang. During inspection, observations are made for vitality, skin color, and the general appearance and the condition of the tongue. For example, a pale complexion corresponds internally to the Lung of autumn, whose Qi is dry. This may occur when Yang Qi is lacking and the circulation of Qi and blood is impeded, or when the coldness in the channels and collaterals causes them to contract.
In TCM, it is from Qi, blood, and body fluid that come energy needed by the Viscera and Bowels, Channels and Collaterals, tissues, and other organs for carrying-out their physiological functions; and on which the formation and metabolism of Qi, blood and body fluid depend. Prescriptions of TCM consider the herbal effects on Qi and blood for treatments.
TCM holds that Channels, Collaterals, and their subsidiary parts are distributed over the entire body It is through them that herbs exert influence on pathological targets and achieve the improvement of sickness. For example, ephedra acts on the Channels of the Lung and Urinary Bladder so as to induce sweat for relieving asthma and promoting diuresis. As noted above, clinical applications of acupuncture are also guided by the theory of Channels and Collaterals.
In summary, while the nature or property of each herb in TCM may be assigned as Yin or Yang, and to one of the Five Elements, they act through Channels and Collaterals and are mediated via Qi, Blood and Fluid to yield therapeutic effects on targets, such as Viscera and Bowels. Pathogenic factors may be disguised as decoys through the very same systems of Channels and Collaterals to adversely affect the functions of Viscera and Bowels and thus cause sickness.
The Patenting of Herbal Compositions in the United States
U.S. Patents have been issued for herbal compositions used for the treatment of various diseases and other health-related problems afflicting mammals, including humans. For example, herbal compositions which include Paeonia suffuticosa have been found useful for treating viral infections, including infection from herpes and polio virus (U.S. Pat. No. 5,411,733).
Ocular inflammation can be treated with a pharmaceutical composition containing the plant alkaloid tetrandrine (U.S. Pat. No. 5,627,195). U.S. Pat. No. 5,683,697 discloses a pharmaceutical composition having anti-inflammatory, anti-fever, expectorant or anti-tussive action, wherein the composition includes plant parts from the species Melia, Angepica, Dendrobium, Impatiens, Citrus, Loranthus, Celosia, Cynanchum and Glehnia. An herbal formulation comprising extracts of the roots, rhizomes, and/or vegetation of Alphinia, Smilax, Tinospora, Tribulus, Withania and Zingiber has been found to reduce or alleviate the symptoms associated with rheumatoid arthritis, osteoarthritis, and reactive arthritis and to reduce the production of proinflammatory cytokines (U.S. Pat. No. 5,683,698). Compositions containing talc, silkworm excrement, and the ingredients of twelve different herbs have been shown to be effective in reducing inflammation, pain, and fever in mammals (U.S. Pat. No. 5,908,628).
Patents have also been issued for herbal compositions which find use in the treatment of cancer and cancer-related health problems. For example, U.S. Pat. No. 5,437,866 discloses a composition comprising a mixture of herbs, including species of Scutellaria barbata, as well as their extracts, which is used to ameliorate the effects of malignancy in humans. U.S. Pat. No. 5,665,393 discloses various herbal compositions which include Glycyrrhiza glabra L. and Scutellaria baicalensis Georgi, Rabdosia rubescens, and Serenoa repens for the treatment of prostate carcinoma. Further, antitumor herbal compositions include Astragali radix, Paeonia radix, Cinnamomi cortex, Rhemannia radi and Glycyrrhizae radix for use in increasing antitumor activity of mitomycin D and doxorubicin (U.S. Pat. No. 4,613,591 and U.S. Pat. No. 4,618,495).
Cancer and the Adverse Effects of Cancer Chemotherapy.
Cancer remains the second overall cause of death in the United States. There is an interest for a method for treating gastrointestinal cancers, including colorectal, liver, and pancreatic cancers, not because of their high incidence rates but rather, because of the high mortality rates, especially of pancreatic and liver cancer patients (Bergsland et al. Current Opinion in Oncology, 12: 357-361 (2000); Fernandez-et al. Curr Opin Gastroenterol, 18: 563-567 (2002); Jemal et al. Cancer J Clin, 52: 23-47 (2002); Skolnick et al., The Journal of the AMerican Medical Association, 276: 1457-1458 (1996)). From years 1992-1999, the study revealed that the five-year relative survival rates of colorectal cancer was 62.3% while that of liver cancer was 6.9% and 4.4% for pancreatic cancer. The median survivals of liver cancer was 3.5 weeks to 6 months while it was 4 to 6 months for pancreatic cancer (Jemal et al. Cancer J Clin, 52: 23-47 (2002)). With only very poor chemotherapeutic regimens available, pancreatic cancer has the highest mortality rate among all cancers in the United States, with a less than 5% survival rate 5 years from diagnosis (Jemal et al. Cancer J Clin, 52: 23-47 (2002)). Although several regimens are currently used in the clinical trials for hepatocellular carcinoma, there is no FDA-approved chemotherapeutic agent available. The low survival rates for both pancreatic and hepatocellular cancers are because diagnosis is difficult, the tumor growth is highly aggressive, surgical removal of tumor is of low probability, and the tumor has a high rate of chemotherapy resistance.
Gemcitabine is the only clinically approved chemotherapeutic agent for pancreatic cancer; however, the response rate in patients to gemcitabine is only 6-11% and the overall survival time is generally 4-6 months. Gemcitabine is a nucleoside analog with two mechanisms of action, including the inhibition of ribonucleotide reductase, an enzyme that converts nucleotide diphosphate to deoxynucleotide triphosphate and that is required for DNA synthesis and that competes with deoxycytidine triphosphate as a fraudulent base in DNA synthesis (Jemal et al., CA Cancer J Clin, 52: 23-47, 2002; Abbruzzese et al., Cancer Supplement, 95: 941-945, 2002; Hertel et al., Cancer Res., 50: 4417-4422, 1990; Pettersson et al., Pancreas, 23: 273-279, 2001; Philip et al., Cancer Supplement, 95: 908-911, 2002; Schultz et al., Oncology Research, 5: 223-228, 1993; Von Hoff et al., Current Opinion in Oncology, 14: 621-627, 2002). With the low response and survival rates of gemcitabine monotherapy, several gemcitabine-combination drug regimens have been tested clinically for improving therapeutic efficacy. These trials include gemcitabine with other commonly used and FDA-approved anti-cancer drugs including CPT-11, capecitabine and oxaliplatin (Bruns et al., Clinical Cancer Research, 6: 1936-1948, 2000; Jacobs et al., Cancer Supplement, 95: 923-927, 2002; Mcginn et al., Cancer Supplement, 95: 933-940, 2002; Oettle et al., Cancer Supplement, 95: 912-922, 2002). Unfortunately, no satisfactory combination drug regimens have been discovered and an effective regimen for pancreatic cancer is urgently needed.
Hepatocellular carcinoma is currently treated by surgical procedures and chemotherapy. Surgical removal and postoperative therapies may improve the outlook for some patients. Unfortunately, the vast majority of patients with hepatocellular carcinoma will have unresectable cancers. Although several regimens are currently used in the clinical trials for hepatocellular carcinoma, there is no FDA-approved chemotherapeutic agent available. Systemic chemotherapy has historically been of little to no value, although 5-fluorouracil (5-FU) and adriamycin (ADM) have demonstrated response rates from 10 to 20% (Suart et al., Am. J. Clin. Oncol., 19: 136-139, 1996). Capecitabine (Xeloda®) is rationally designed to be efficiently absorbed from the gastrointestinal tract as an oral prodrug and converted to 5-FU, preferentially in neoplastic tissues. Currently, capecitabine is approved as firstline therapy for the treatment of colorectal cancer and breast cancer with reduced toxicities (Berg et al., Semin. Oncol., 25: 53-59, 1998; Schwetz et al., JAMA, 286: 2085, 2001). Capecitabine is potentially an exciting new therapeutic agent. Although sharing the similar clinical response (13%) as 5-FU or ADM in liver cancer, capecitabine has distinct advantages, such as being an orally administered drug with relatively low toxicity that will improve the quality of life for hepatocellular carcinoma patients (Aguayo et al., Seminars In Oncology, 28: 503-513, 2001; Leung et al., Seminars In Oncology, 28: 514-520, 2001; Lozano et al, Oral Capecitabine (Xeloda®) for the Treatment of Hepatobillary Cancers (Hepatocellular Carcinoma, Cholangiocarcinoma, and Gallbladder Cancer). 19. 2000. Proceedings of ASCO).
Colorectal cancer has been reported to be the third most common cause of death from cancer in the United States (ACS Cancer Facts and Figures. American Cancer Society, 2004). Recently, the FDA approved the triple combination use of Oxaliplatin/5-FU/LV as firstline treatment for patients with advanced colorectal cancer. Oxaliplatin is a synthesized diaminocyclohexane platinum compound, which like cisplatin, causes platinum-DNA adduct formation and destroys the integrity of DNA (Eric Raymond et al., Molecular Cancer Therapeutics, 1: 227-235, 2002). Other types of chemotherapeutic agents, such as 5-FU, CPT-11, are common chemotherapeutic agents used in the treatment of colorectal cancer. Unfortunately, severe diarrhea has been identified as one of the dose-limiting toxicities among patients treated with chemotherapy.
Medical oncology has had a great impact in changing the practice of medicine in the past several decades as curative treatments for a variety of previously fatal malignancies have been identified. However, few categories of drugs in common use have a narrower therapeutic index and a greater potential for causing harmful side effects than do the antineoplastic drugs (Calabresi and Chabner, 1996).
Anticancer agents, like many other potent drugs with only moderate selectivity, may cause severe toxicity. Common adverse effects associated with cancer chemotherapy include, but are not limited to, gastrointestinal complications (e.g., diarrhea, nausea, vomiting, anorexia and mucositis), pain, appetite loss, bone marrow/hematologic complications (e.g., leukopenia, neutropenia, anemia, hemorrhage, thrombocytopenia), fatigue and sleep disturbance.
The inventors of the present invention performed a literature search for Chinese medicinal formulations that have been used for the treatment of symptoms associated with cancer chemotherapy. TJ-14, a botanical formulation with seven herbs, was reported to potently prevent diarrhea caused by CPT-11 in cancer patients (Kase, Y, Hayakawa T, and Aburada M. et al., Jpn. J. Pharmacol. 75, 407-413 (1997); Marita M., Nagai E and Hagiwara H. et al., Xenobiotica. 23, 5-10 (1993)). The diarrhea was hypothesized to occur from the accumulation of SN-38, an active metabolite of CPT-11, created by intestinal microorganisms. The inventors believe that baicalin, an inhibitor of β-glucuronidase, is the active ingredient in TJ-14 that alleviates diarrhea caused by CPT-11 (Kase, Y, Hayakawa T, and Aburada M. et al., Jpn. J. Pharmacol. 75, 407-413 (1997); Marita M., Nagai E and Hagiwara H. et al., Xenobiotica. 23, 5-10 (1993); Takasuna K, Takehiro H, Hirohashi M, et al., Cancer Chemother Pharmacol. 42:280-286 (1998); Takasuna K, Takehiro H, Hirohashi M, Kato M, et al., Cancer Res. 56:3752-3757 (1996)). Therefore, several Chinese herbal formulations containing the root of Scuellaria baicalensis Georgi, which is rich in baicalin, were evaluated. Among several formulations examined in the laboratory, the inventors chose PHY906. This specific formulation was established more than 1500 years ago for the treatment of diarrhea, abdominal spasms, fever, headache, vomiting, nausea, extreme thirst, and subcardial distention (Shang Han Lun of the Han Dynasty; Hong-Yen Hsu and Chau-Shin Hsu, Commonly used Chinese Herb Formulas with Illustrations, Oriental Healing Art Institute, California, (1980)). PHY906 consists of four herbs with proportion of Scutellariae baicalensis Georgi (scute), Paeonia lactiflora pall (white peony root), Glycyrrhizae uralensis Fisch (licorice) and the fruit of Fructus ziziphi (date) mixed in the proportions 1.5:1.0:1.0:1.0 by dry weight, respectively. It should be noted that each herb possesses a distinct pharmacological profile that includes anticancer and antiviral activity, hematological and immunological stimulation, analgesic activity, vasodilation, liver protection, antioxidation, and appetite improvement, as shown in Table 1.
TABLE 1Putative Biological Activities of Individual Herbs in the PHY906 Formulation.Anti-Anti-Anti-NervousCancerImmuno-ModulationBacteriaInflammatorySystemOthersScuellaria++++−antiviral, antibacterial antidiarrhea, diuretic,baicalensis↑↓ lymphocyte &vasodilation, ↓ lipid, anticoagulation,Georgimacrophage activityantioxidant, antiemetic, liver protectionbifunctionalPaeonia+++++vasodilation, liver protection, diureticlactiflora pall↑↓ macrophage activityanalgesicanticoagulation, ↓ intestine movementbifunctional modulatorFructus ziziphi++−−+liver protection, muscle endurance,anti IgE action↑ sleepimprove appetiteGlycyrrhiza+++++Antidiureticuralensis Fisch↑ macrophage activityanalgesic↓ intestine movement↑ interferon &↑ IL-1↓ lipid (LDL, TC)↑ lymphocyteantioxidant↑ interferon &↑ IL-2antiviral↑ NK activityanticoagulation↓ IgEanticomplement↑: increase↓: decrease↑↓: decrease or increase+: effect−: no effect
Until now, PHY906 has been prescribed as a single medicine only, rather than in combination with synthetic drugs. However, it is conceivable that one of the documented uses of PHY906 might actually be useful in alleviating the side effects induced by chemotherapy. Although some of the major chemical components in each of the four herbs of PHY906 have been identified, and their pharmacological activities have been examined (Chinese Botany Shanghai Science and Technology Publishing Company (1999); Huang, H-C, Wang, H-R, and Hsieh, L-M., Eur J of Pharmacol 251:91-93 (1994); Lin, C-C and Shieh, Am J Chinese Med 1:31-36 (1996); Tang, W. and Eisenbrand, G., Chinese Drugs of Plant Origin: Chemistry, Pharmacology and Use in Traditional and Modern Medicine pp. 919-929. Springer-Verlag Press, New York, (1992)), the biological properties of PHY906 may not be fully predicted by the identified ingredients.